PCA outperforms popular hidden variable inference methods for molecular QTL mapping

BACKGROUND: Estimating and accounting for hidden variables is widely practiced as an important step in molecular quantitative trait locus (molecular QTL, henceforth “QTL”) analysis for improving the power of QTL identification. However, few benchmark studies have been performed to evaluate the efficacy of the various methods developed for this purpose. RESULTS: Here we benchmark popular hidden variable inference methods including surrogate variable analysis (SVA), probabilistic estimation of expression residuals (PEER), and hidden covariates with prior (HCP) against principal component analysis (PCA)—a well-established dimension reduction and factor discovery method—via 362 synthetic and 110 real data sets. We show that PCA not only underlies the statistical methodology behind the popular methods but is also orders of magnitude faster, better-performing, and much easier to interpret and use. CONCLUSIONS: To help researchers use PCA in their QTL analysis, we provide an R package PCAForQTL along with a detailed guide, both of which are freely available at https://github.com/heatherjzhou/PCAForQTL. We believe that using PCA rather than SVA, PEER, or HCP will substantially improve and simplify hidden variable inference in QTL mapping as well as increase the transparency and reproducibility of QTL research. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-022-02761-4.